17-63918770-T-G

Variant names:

• chr17-63918770-T-G
• rs2001345
• NM_000515.5:c.7A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000515.5(GH1):​c.7A>C​(p.Thr3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.06
• Publications: 10 publications found

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

GH1 Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short stature due to growth hormone qualitative anomaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285947 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024536937).
• BP6: Variant 17-63918770-T-G is Benign according to our data. Variant chr17-63918770-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 452376.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152284) while in subpopulation NFE AF = 0.000529 (36/68014). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	NM_000515.5	MANE Select	c.7A>C	p.Thr3Pro	missense	Exon 1 of 5	NP_000506.2
	GH1	NM_022559.4		c.7A>C	p.Thr3Pro	missense	Exon 1 of 5	NP_072053.1
	GH1	NM_022560.4		c.7A>C	p.Thr3Pro	missense	Exon 1 of 4	NP_072054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.7A>C	p.Thr3Pro	missense	Exon 1 of 5	ENSP00000312673.5
	GH1	ENST00000458650.6	TSL:1	c.7A>C	p.Thr3Pro	missense	Exon 1 of 5	ENSP00000408486.2
	ENSG00000285947	ENST00000647774.1		c.287-264A>C		intron	N/A	ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 249884 AF XY: 0.000222

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1460778 Hom.: 0 Cov.: 35 AF XY: 0.000263 AC XY: 191 AN XY: 726758

African (AFR) AF: 0.000209 AC: 7 AN: 33422

American (AMR) AF: 0.000179 AC: 8 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86236

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.000283 AC: 314 AN: 1111062

Other (OTH) AF: 0.000315 AC: 19 AN: 60348

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74478

African (AFR) AF: 0.000457 AC: 19 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000119 Hom.: 1

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.8
DANN	Benign	0.32
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.33
Sift	Benign	0.65	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.22
MPC		0.14
ClinPred		0.0013	T
GERP RS		-0.16
PromoterAI		-0.011	Neutral
Varity_R		0.10
gMVP		0.23
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2001345; hg19: chr17-61996130;